Clinical Orthopaedics and Related Research®

, Volume 467, Issue 12, pp 3257–3262 | Cite as

Complications of Recombinant Human BMP-2 for Treating Complex Tibial Plateau Fractures: A Preliminary Report

  • Sreevathsa Boraiah
  • Omesh Paul
  • David Hawkes
  • Matthew Wickham
  • Dean G. Lorich
Symposium: Tribute to Dr. Marshall Urist: Musculoskeletal Growth Factors

Abstract

Bone morphogenic proteins (BMPs) are potent osteoinductive agents. Their use in fracture surgery is still being studied and the clinical indications are evolving. Heterotopic bone after BMP use in spine surgery is a known complication. While some literature describes the ability of BMP to enhance fracture healing, few articles describe complications of BMP. In tibial plateau fractures, after elevating the cartilage en mass, a subchondral void may be created in these fractures. Structural support provided by bone void-filling agents can be augmented with osteoinduction achieved by BMP. We asked whether heterotopic bone formation would occur more frequently with BMP-2 when used in tibial plateau fractures and whether BMP-2 enhanced the ability to maintain surgically restored subchondral bone integrity. Heterotopic bone developed more frequently in patients receiving BMP (10 of 17) than in patients not receiving BMP (one of 23). Four patients receiving BMP and no patients not receiving BMP underwent removal of heterotopic bone. Maintenance of subchondral bone integrity was similar without and with the use of BMP. BMP is a potent osteoinductive agent; however, when used for an off-label indication in periarticular situations, complications such as heterotopic bone are common and increase reoperation rates.

Level of Evidence: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

References

  1. 1.
    Apley AG. Fractures of the tibial plateau. Orthop Clin North Am. 1979;10:61–74.PubMedGoogle Scholar
  2. 2.
    Baas J, Elmengaard B, Jensen TB, Jakobsen T, Andersen NT, Soballe K. The effect of pretreating morselized allograft bone with rhBMP-2 and/or pamidronate on the fixation of porous Ti and HA-coated implants. Biomaterials. 2008;29:2915–2922.CrossRefPubMedGoogle Scholar
  3. 3.
    Benglis D, Wang MY, Levi AD. A comprehensive review of the safety profile of bone morphogenetic protein in spine surgery. Neurosurgery. 2008;62(5 suppl 2):ONS423–ONS431; discussion ONS431.PubMedCrossRefGoogle Scholar
  4. 4.
    Blokker CP, Rorabeck CH, Bourne RB. Tibial plateau fractures: an analysis of the results of treatment in 60 patients. Clin Orthop Relat Res. 1984;182:193–199.PubMedGoogle Scholar
  5. 5.
    Bouxsein ML, Turek TJ, Blake CA, D’Augusta D, Li X, Stevens M, Seeherman HJ, Wozney JM. Recombinant human bone morphogenetic protein-2 accelerates healing in a rabbit ulnar osteotomy model. J Bone Joint Surg Am. 2001;83:1219–1230.PubMedGoogle Scholar
  6. 6.
    Boyne PJ. Animal studies of application of rhBMP-2 in maxillofacial reconstruction. Bone. 1996;19(1 suppl):83S–92S.CrossRefPubMedGoogle Scholar
  7. 7.
    Boyne PJ, Marx RE, Nevins M, Triplett G, Lazaro E, Lilly LC, Alder M, Nummikoski P. A feasibility study evaluating rhBMP-2/absorbable collagen sponge for maxillary sinus floor augmentation. Int J Periodontics Restorative Dent. 1997;17:11–25.PubMedGoogle Scholar
  8. 8.
    Brower RS, Vickroy NM. A case of psoas ossification from the use of BMP-2 for posterolateral fusion at L4–L5. Spine. 2008;33:E653–E655.CrossRefPubMedGoogle Scholar
  9. 9.
    Burkus JK, Dorchak JD, Sanders DL. Radiographic assessment of interbody fusion using recombinant human bone morphogenetic protein type 2. Spine. 2003;28:372–377.CrossRefPubMedGoogle Scholar
  10. 10.
    Burkus JK, Transfeldt EE, Kitchel SH, Watkins RG, Balderston RA. Clinical and radiographic outcomes of anterior lumbar interbody fusion using recombinant human bone morphogenetic protein-2. Spine. 2002;27:2396–2408.CrossRefPubMedGoogle Scholar
  11. 11.
    Dimar JR, Glassman SD, Burkus KJ, Carreon LY. Clinical outcomes and fusion success at 2 years of single-level instrumented posterolateral fusions with recombinant human bone morphogenetic protein-2/compression resistant matrix versus iliac crest bone graft. Spine. 2006;31:2534–2539; discussion 2540.CrossRefPubMedGoogle Scholar
  12. 12.
    Downes S, Patel M, Di Silvio L, Swai H, Davy K, Braden M. Modifications of the hydrophilicity of heterocyclic methacrylate copolymers for protein release. Biomaterials. 1995;16:1417–1421.CrossRefPubMedGoogle Scholar
  13. 13.
    Friedlaender GE, Perry CR, Cole JD, Cook SD, Cierny G, Muschler GF, Zych GA, Calhoun JH, LaForte AJ, Yin S. Osteogenic protein-1 (bone morphogenetic protein-7) in the treatment of tibial nonunions. J Bone Joint Surg Am. 2001;83(suppl 1 pt 2):S151–S158.PubMedGoogle Scholar
  14. 14.
    Fu YC, Nie H, Ho ML, Wang CK, Wang CH. Optimized bone regeneration based on sustained release from three-dimensional fibrous PLGA/HAp composite scaffolds loaded with BMP-2. Biotechnol Bioeng. 2008;99:996–1006.CrossRefPubMedGoogle Scholar
  15. 15.
    Govender S, Csimma C, Genant HK, Valentin-Opran A, Amit Y, Arbel R, Aro H, Atar D, Bishay M, Borner MG, Chiron P, Choong P, Cinats J, Courtenay B, Feibel R, Geulette B, Gravel C, Haas N, Raschke M, Hammacher E, van der Velde D, Hardy P, Holt M, Josten C, Ketterl RL, Lindeque B, Lob G, Mathevon H, McCoy G, Marsh D, Miller R, Munting E, Oevre S, Nordsletten L, Patel A, Pohl A, Rennie W, Reynders P, Rommens PM, Rondia J, Rossouw WC, Daneel PJ, Ruff S, Ruter A, Santavirta S, Schildhauer TA, Gekle C, Schnettler R, Segal D, Seiler H, Snowdowne RB, Stapert J, Taglang G, Verdonk R, Vogels L, Weckbach A, Wentzensen A, Wisniewski T. Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am. 2002;84:2123–2134.CrossRefPubMedGoogle Scholar
  16. 16.
    Issa JP, Bentley MV, Iyomasa MM, Sebald W, De Albuquerque RF. Sustained release carriers used to delivery bone morphogenetic proteins in the bone healing process. Anat Histol Embryol. 2008;37:181–187.CrossRefPubMedGoogle Scholar
  17. 17.
    Jones AL, Bucholz RW, Bosse MJ, Mirza SK, Lyon TR, Webb LX, Pollak AN, Golden JD, Valentin-Opran A. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects: a randomized, controlled trial. J Bone Joint Surg Am. 2006;88:1431–1441.CrossRefPubMedGoogle Scholar
  18. 18.
    Jones CB, Sabatino CT, Badura JM, Sietsema DL, Marotta JS. Improved healing efficacy in canine ulnar segmental defects with increasing recombinant human bone morphogenetic protein-2/allograft ratios. J Orthop Trauma. 2008;22:550–559.CrossRefPubMedGoogle Scholar
  19. 19.
    Joseph V, Rampersaud YR. Heterotopic bone formation with the use of rhBMP2 in posterior minimal access interbody fusion: a CT analysis. Spine. 2007;32:2885–2890.CrossRefPubMedGoogle Scholar
  20. 20.
    Kannan RY, Salacinski HJ, Sales K, Butler P, Seifalian AM. The roles of tissue engineering and vascularisation in the development of micro-vascular networks: a review. Biomaterials. 2005;26:1857–1875.CrossRefPubMedGoogle Scholar
  21. 21.
    Katsuno Y, Hanyu A, Kanda H, Ishikawa Y, Akiyama F, Iwase T, Ogata E, Ehata S, Miyazono K, Imamura T. Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. Oncogene. 2008;27:6322–6333.CrossRefPubMedGoogle Scholar
  22. 22.
    Kempen DH, Lu L, Heijink A, Hefferan TE, Creemers LB, Maran A, Yaszemski MJ, Dhert WJ. Effect of local sequential VEGF and BMP-2 delivery on ectopic and orthotopic bone regeneration. Biomaterials. 2009;30:2816–2825.CrossRefPubMedGoogle Scholar
  23. 23.
    Kettelkamp DB, Hillberry BM, Murrish DE, Heck DA. Degenerative arthritis of the knee secondary to fracture malunion. Clin Orthop Relat Res. 1988;234:159–169.PubMedGoogle Scholar
  24. 24.
    Krause F, Younger A, Weber M. Recombinant human BMP-2 and allograft compared with autogenous bone graft for reconstruction of diaphyseal tibial fractures with cortical defects. J Bone Joint Surg Am. 2008;90:1168; author reply 1168–1169.PubMedGoogle Scholar
  25. 25.
    Lansinger O, Bergman B, Korner L, Andersson GB. Tibial condylar fractures: a twenty-year follow-up. J Bone Joint Surg Am. 1986;68:13–19.PubMedGoogle Scholar
  26. 26.
    Lee FY, Sinicropi SM, Lee FS, Vitale MG, Roye DP Jr, Choi IH. Treatment of congenital pseudarthrosis of the tibia with recombinant human bone morphogenetic protein-7 (rhBMP-7): a report of five cases. J Bone Joint Surg Am. 2006;88:627–633.CrossRefPubMedGoogle Scholar
  27. 27.
    Lee SH, Shin H. Matrices and scaffolds for delivery of bioactive molecules in bone and cartilage tissue engineering. Adv Drug Deliv Rev. 2007;59:339–359.CrossRefPubMedGoogle Scholar
  28. 28.
    Li RH, Wozney JM. Delivering on the promise of bone morphogenetic proteins. Trends Biotechnol. 2001;19:255–265.CrossRefPubMedGoogle Scholar
  29. 29.
    Lyons KM, Pelton RW, Hogan BL. Patterns of expression of murine Vgr-1 and BMP-2a RNA suggest that transforming growth factor-beta-like genes coordinately regulate aspects of embryonic development. Genes Dev. 1989;3:1657–1668.CrossRefPubMedGoogle Scholar
  30. 30.
    McKay WF, Peckham SM, Badura JM. A comprehensive clinical review of recombinant human bone morphogenetic protein-2 (INFUSE Bone Graft). Int Orthop. 2007;31:729–734.CrossRefPubMedGoogle Scholar
  31. 31.
    Nordsletten L. Recent developments in the use of bone morphogenetic protein in orthopaedic trauma surgery. Curr Med Res Opin. 2006;22(suppl 1):S13–S17; S23.CrossRefPubMedGoogle Scholar
  32. 32.
    Perri B, Cooper M, Lauryssen C, Anand N. Adverse swelling associated with use of rh-BMP-2 in anterior cervical discectomy and fusion: a case study. Spine J. 2007;7:235–239.CrossRefPubMedGoogle Scholar
  33. 33.
    Poynton AR, Lane JM. Safety profile for the clinical use of bone morphogenetic proteins in the spine. Spine. 2002;27(16 suppl 1):S40–S48.CrossRefPubMedGoogle Scholar
  34. 34.
    Rasmussen PS. Tibial condylar fractures: impairment of knee joint stability as an indication for surgical treatment. J Bone Joint Surg Am. 1973;55:1331–1350.PubMedGoogle Scholar
  35. 35.
    Reddi AH, Cunningham NS. Bone induction by osteogenin and bone morphogenetic proteins. Biomaterials. 1990;11:33–34.PubMedGoogle Scholar
  36. 36.
    Ristiniemi J, Flinkkila T, Hyvonen P, Lakovaara M, Pakarinen H, Jalovaara P. RhBMP-7 accelerates the healing in distal tibial fractures treated by external fixation. J Bone Joint Surg Br. 2007;89:265–272.CrossRefPubMedGoogle Scholar
  37. 37.
    Sarmiento A, Kinman PB, Latta LL, Eng P. Fractures of the proximal tibia and tibial condyles: a clinical and laboratory comparative study. Clin Orthop Relat Res. 1979;145:136–145.PubMedGoogle Scholar
  38. 38.
    Schatzker J, McBroom R, Bruce D. The tibial plateau fracture: the Toronto experience 1968–1975. Clin Orthop Relat Res. 1979;138:94–104.PubMedGoogle Scholar
  39. 39.
    Schmidmaier G, Schwabe P, Strobel C, Wildemann B. Carrier systems and application of growth factors in orthopaedics. Injury. 2008;39(suppl 2):S37–S43.CrossRefPubMedGoogle Scholar
  40. 40.
    Sciadini MF, Johnson KD. Evaluation of recombinant human bone morphogenetic protein-2 as a bone-graft substitute in a canine segmental defect model. J Orthop Res. 2000;18:289–302.CrossRefPubMedGoogle Scholar
  41. 41.
    Shields LB, Raque GH, Glassman SD, Campbell M, Vitaz T, Harpring J, Shields CB. Adverse effects associated with high-dose recombinant human bone morphogenetic protein-2 use in anterior cervical spine fusion. Spine. 2006;31:542–547.CrossRefPubMedGoogle Scholar
  42. 42.
    Swiontkowski MF, Aro HT, Donell S, Esterhai JL, Goulet J, Jones A, Kregor PJ, Nordsletten L, Paiement G, Patel A. Recombinant human bone morphogenetic protein-2 in open tibial fractures: a subgroup analysis of data combined from two prospective randomized studies. J Bone Joint Surg Am. 2006;88:1258–1265.CrossRefPubMedGoogle Scholar
  43. 43.
    Uludag H, Gao T, Porter TJ, Friess W, Wozney JM. Delivery systems for BMPs: factors contributing to protein retention at an application site. J Bone Joint Surg Am. 2001;83(suppl 1 pt 2):S128–S135.PubMedGoogle Scholar
  44. 44.
    Urist MR, Mikulski A, Lietze A. Solubilized and insolubilized bone morphogenetic protein. Proc Natl Acad Sci USA. 1979;76:1828–1832.CrossRefPubMedGoogle Scholar
  45. 45.
    Urist MR, Silverman BF, Buring K, Dubuc FL, Rosenberg JM. The bone induction principle. Clin Orthop Relat Res. 1967;53:243–283.CrossRefPubMedGoogle Scholar
  46. 46.
    Vaccaro AR, Anderson DG, Patel T, Fischgrund J, Truumees E, Herkowitz HN, Phillips F, Hilibrand A, Albert TJ, Wetzel T, McCulloch JA. Comparison of OP-1 putty (rhBMP-7) to iliac crest autograft for posterolateral lumbar arthrodesis: a minimum 2-year follow-up pilot study. Spine. 2005;30:2709–2716.CrossRefPubMedGoogle Scholar
  47. 47.
    Vaccaro AR, Lawrence JP, Patel T, Katz LD, Anderson DG, Fischgrund JS, Krop J, Fehlings MG, Wong D. The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft in posterolateral lumbar arthrodesis: a long-term (>4 years) pivotal study. Spine. 2008;33:2850–2862.CrossRefPubMedGoogle Scholar
  48. 48.
    Vaccaro AR, Whang PG, Patel T, Phillips FM, Anderson DG, Albert TJ, Hilibrand AS, Brower RS, Kurd MF, Appannagari A, Patel M, Fischgrund JS. The safety and efficacy of OP-1 (rhBMP-7) as a replacement for iliac crest autograft for posterolateral lumbar arthrodesis: minimum 4-year follow-up of a pilot study. Spine J. 2008;8:457–465.CrossRefPubMedGoogle Scholar
  49. 49.
    Valentin-Opran A, Wozney J, Csimma C, Lilly L, Riedel GE. Clinical evaluation of recombinant human bone morphogenetic protein-2. Clin Orthop Relat Res. 2002;395:110–120.CrossRefPubMedGoogle Scholar
  50. 50.
    Wong DA, Kumar A, Jatana S, Ghiselli G, Wong K. Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine J. 2008;8:1011–1018.CrossRefPubMedGoogle Scholar
  51. 51.
    Wozney JM, Rosen V, Celeste AJ, Mitsock LM, Whitters MJ, Kriz RW, Hewick RM, Wang EA. Novel regulators of bone formation: molecular clones and activities. Science. 1988;242:1528–1534.CrossRefPubMedGoogle Scholar

Copyright information

© The Association of Bone and Joint Surgeons® 2009

Authors and Affiliations

  • Sreevathsa Boraiah
    • 1
  • Omesh Paul
    • 1
  • David Hawkes
    • 2
  • Matthew Wickham
    • 2
  • Dean G. Lorich
    • 1
  1. 1.Department of Orthopaedic SurgeryHospital for Special SurgeryNew YorkUSA
  2. 2.University of Liverpool Medical SchoolLiverpoolUK

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